Glaucoma is a leading cause of blindness and visual disability that has a major impact on the quality of life and productivity of millions of Americans. Glaucoma is defined by quantitative traits including, optic nerve cupping, visual field loss, and central corneal thickness. Intraocular pressure is another crucial quantitative trait that is monitored in glaucoma patients. The cascade of events that lead to glaucoma is not well known, which has hindered efforts for early detection and treatment of this condition. One way to investigate the pathogenesis of glaucoma is to identify disease-causing genes. Glaucoma is a heterogeneous disease and is likely caused by the interactions of many genes. This complexity has challenged efforts to identify genes that cause glaucoma. As a result, there is a critical need for research that focuses on glaucoma phenotypes with reduced complexity to facilitate the discovery of disease-causing genes. Our long-term goal is to identify and define pathways that lead from DNA variations in the genome to the vision loss of glaucoma. As stages of glaucoma pathogenesis are discovered, new interventions to prevent vision loss will become possible. Several quantitative features of the glaucoma phenotype (cup-to-disc ratio, corneal thickness, and intraocular pressure) are each independently associated with glaucoma and highly heritable. We hypothesize that the same genes that determine the magnitudes of these features of glaucoma will also be important in the pathogenesis of glaucoma overall. Furthermore, a single feature of glaucoma has less complexity than the whole disease. This reduced complexity will facilitate discovery of genetic factors for components of the glaucoma phenotype. Genes that control quantitative traits of glaucoma will be identified with studies of human cohorts and inbred mice. The Ocular Hypertension Treatment Study (OHTS) is a large treatment trial designed to show the efficacy of treating patients with high intraocular pressure. We will identify genetic factors that control the magnitude of cup-to-disc ratio, intraocular pressure, and corneal thickness by conducting a genome-wide association study of the patients in this trial (Specific Aim 1). Quantitative traits are often determined by the actions of many genetic factors. Studies of inbred mice with fixed genetic backgrounds have the advantage of reducing the complexity of these traits. By crossing inbred strains, specific risk alleles that determine a quantitative trait may be more easily recognized against the uniform genetic background. Therefore, we will study the genetic basis of an important quantitative feature of glaucoma (central corneal thickness) with crosses of inbred mice (Specific Aim 2). We expect that our proposed studies will identify new risk alleles for quantitative features of glaucoma. The discovery of such risk alleles will have an important impact on the future clinical management of glaucoma by facilitating early diagnosis and enabling the development of new sight- saving treatments. PUBLIC HEALTH RELEVANCE: Although glaucoma is a heritable cause of blindness that affects millions of Americans, little is known about the genetic risk factors that contribute to this condition. We propose experiments that will identify genes that control component features of the overall glaucoma phenotype. These discoveries will provide insight into the biological pathways that lead to disease and will also facilitate improved diagnosis, prognosis, and treatments for those with this debilitating condition.